Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

Abstract

Purpose Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy. Methods Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected. Results 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI. Conclusion A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.

Significance of molecular diagnostics for therapeutic decision-making in recurrent glioma

“…Within our cohort of 73 recurrent glioma patients, we observed actionable mutations in 68.5% of the cases and targeted therapy was administered in 24% of these patients, which is in line with previous studies for neuro-oncologic patients. 15 , 16 , 23 However, in comparison to other solid tumor entities like pancreatic cancer (26%) 27 or extrahepatic cholangiocarcinoma (40%) 28 we detected a higher number of actionable targets highlighting the great variety of molecular-based treatment options for glioma patients. However, the assessment of the clinical utility of targeted therapies is not easy to define as molecular-based targeted therapies are mainly used at various stages of the disease.…”

“…According to Luger et al 2 groups were defined: One group comprising all patients with at least SD at first follow-up MRI scan and another group with PD at first MRI. 15 Median PFS of patients with at least SD was 338 days (range 119–343 days) and 55 days (range 9–126 days) for patients with PD at first follow-up ( P < .01) ( Figure 3C ). However, the cohort with PD at first MRI scan comprises a higher proportion of CNS WHO grade 4 tumors (1 patient in SD group, 3 patients in PD group).…”

“… 12–14 However, due to a lack of therapeutic options, molecularly matched off-label treatments are considered after discussion in molecular tumor boards for patients with relapsing glioma in a good condition in many centers across Europe and even reimbursement can be granted by health insurances. 15 , 16 …”

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

“…These data suggest that there is a trend towards RAS–MAPK pathway alterations in ATRX-deficient high-grade gliomas. According to recent observations, variants of RAS–MAPK pathway components, in particular, BRAF mutations, seem to be the most promising actionable targets in brain tumors 32 . Furthermore, abnormalities in this pathway are significantly enriched in GBs responding to immunotherapy 29 and NF1 mutation has been shown to induce an immunosuppressive, macrophage-microglia rich microenvironment in gliomas 33 .…”

Artificial Intelligence in Brain Tumor Imaging: A Step toward Personalized Medicine

“…and DNA methylation profiles [ 6 , 7 ]. The genetic and epigenetic makeups define the molecular signature, a “barcode” of the tumor, whose recognition is essential for clinical decision-making in the era of targeted therapies [ 8 ]. Therefore, tissue sampling remains the gold standard for decoding the molecular landscape of most CNS tumors, especially for gliomas [ 9 ].…”